Researchers from Princeton University's Department of Molecular Biology have identified a small RNA molecule that helps maintain the activity of stem cells in both healthy and cancerous breast tissue. The study, which will be published in the June issue of Nature Cell Biology, suggests that this "microRNA" promotes particularly deadly forms of breast cancer and that inhibiting the effects of this molecule could improve the efficacy of existing breast cancer therapies.
Stem cells give rise to the different cell types in adult tissues but, in order to maintain these tissues throughout adulthood, stem cells must retain their activity for decades. They do this by "self-renewing," dividing to form additional stem cells, and resisting the effects of environmental signals that would otherwise cause them to prematurely differentiate into other cell types.
Many tumors also contain so-called "cancer stem cells" that can drive tumor formation. Some tumors, such as triple-negative breast cancers, are particularly deadly because they contain large numbers of cancer stem cells that self-renew and resist differentiation.
To identify factors that help non-cancerous mammary gland stem cells (MaSCs) resist differentiation and retain their capacity to self-renew, Yibin Kang, the Warner-Lambert/Parke-Davis Professor of Molecular Biology, and colleagues searched for short RNA molecules called microRNAs that can bind and inhibit protein-coding messenger RNAs to reduce the levels of specific proteins. The researchers identified one microRNA, called miR-199a, that helps MaSCs retain their stem-cell activity by suppressing the production of a protein called LCOR, which binds DNA to regulate gene expression. The team showed that when they boosted miR-199a levels in mouse MaSCs, they suppressed LCOR and increased normal stem cell function. Conversely, when they increased LCOR levels, they could curtail mammary gland stem cell activity.
Kang and colleagues found that miR-199a was also expressed in human and mouse breast cancer stem cells. Just as boosting miR-199a levels helped normal mammary gland stem cells retain their activity, the researchers showed that miR-199a enhanced the ability of cancer stem cells to form tumors. By increasing LCOR levels, in contrast, they could reduce the tumor-forming capacity of the cancer stem cells. In collaboration with researchers led by Zhi-Ming Shao, a professor at Fudan University Shanghai Cancer Center in China, Kang's team found that breast cancer patients whose tumors expressed large amounts of miR-199a showed poor survival rates, whereas tumors with high levels of LCOR had a better prognosis.
Kang and colleagues found that LCOR sensitizes cells to the effects of interferon-signaling molecules released from epithelial and immune cells, particularly macrophages, in the mammary gland. During normal mammary gland development, these cells secrete interferon-alpha to promote cell differentiation and inhibit cell division, the researchers discovered. By suppressing LCOR, miR-199a protects MaSCs from interferon signaling, allowing MaSCs to remain undifferentiated and capable of self-renewal.
The microRNA plays a similar role during tumorigenesis, protecting breast cancer stem cells from the effects of interferons secreted by immune cells present in the tumor. "This is a very nice study linking a normal and malignant mammary gland stem cell program to protection from immune modulators," said Michael Clarke, the Karel H. and Avice N. Beekhuis Professor in Cancer Biology at Stanford School of Medicine, Institute of Stem Cell Biology and Regenerative Medicine, who first discovered breast cancer stem cells but was not involved in this study. "It clearly has therapeutic implications for designing strategies to rationally target the breast cancer stem cells with immune modulators."
Toni Celià -Terrassa, an associate research scholar in the Kang lab and the first author of the study, said, "This study unveils a new property of breast cancer stem cells that give them advantages in their interactions with the immune system, and therefore it represents an excellent opportunity to exploit for improving immunotherapy of cancer."
"Interferons have been widely used for the treatment of multiple cancer types," Kang said. "These treatments might become more effective if the interferon-resistant cancer stem cells can be rendered sensitive by targeting the miR-199a-LCOR pathway."
Other authors on the paper were Daniel Liu, Abrar Choudhury, Xiang Hang, Yong Wei, Raymundo Alfaro-Aco, Rumela Chakrabarti, Christina DeCoste, Bong Ihn Koh and Heath Smith of the Department of Molecular Biology at Princeton University; Jose Zamalloa of the Department of Molecular Biology and the Lewis-Sigler Institute for Integrative Genomics at Princeton University; and Yi-Zhou Jiang, Jun-Jing Li and Zhi-Ming Shao of the Department of Breast Surgery at Fudan University Shanghai Cancer Center and the Department of Oncology at Shanghai Medical College, Fudan University.

Objective: To elaborate on the clinical and pathologic features of sarcomatoid malignant mesothelioma (SMM), its diagnostic criteria and differential diagnoses. Methods: Twenty-two cases of SMM retrieved from in-house and consultation files (between January 2009 to September 2013) were reviewed with emphasis on the clinicopathologic characteristics, immunophenotypes and the prognostic impact. Results: The mean age of the patients was 54 years (ranged from 24-73 years). There was no sexual predilection and the majority of the patients did not have history of asbestos exposure. Overall, 14 tumors developed in the pleura and 8 cases arose from the peritoneal cavity. Clinically, patients presented signs and symptoms in accord with the location of the tumors, notably coughing, shortness of breath, and chest pain for patients with pleural origin, and nausea, abdominal distention and abdominal pain for those with peritoneal primary. In most cases, CT and MRI scan demonstrated lobulated masses (8/11). However, diffuse infiltrative growth patterns were observed exclusively in a minority of pleural cases (3/11). No visceral lesion was observed in any case. Histologically, 19 cases had either fibrosarcomatous or undifferentiated pleomorphic sarcoma-like appearance. Two cases were consistent with desmoplastic mesothelioma. One case contained osteosarcomatous element. All cases expressed pan-cytokeratin (AE1/AE3), and most cases were also positive for D2-40 (15/20). The staining of calretinin (9/21) and WT1 (10/14) was generally weak and focal. They were all negative for TTF-1, napsin A, SP-A, p63 and CD34. Follow-up information (range from 1 to 36 months) was available in 11 cases, 6 of which were alive with unresectable tumor, 1 patient with recurrent disease and 4 patients succumbed to disease. The overall survival was 5 months (mean 8 months). Conclusions The diagnosis of SMM is achieved by comprehensive evaluation of medical history, imageological and pathological findings. Since calretinin immunoreactivity is infrequently observed in SMM, application of pan-cytokeratin and D2-40 immunostains offers a reasonable alternative for diagnosis. Diagnosis of SMM can be made by excluding a variety of spindle cell neoplasms with overlapping features, such as sarcomatoid carcinoma, synovial sarcoma, solitary fibrous tumor and fibrous pleuritis.

To evaluate the two-tier system for the grading of ovarian serous carcinomas, and to analyze Pax2, p53, Ki-67 protein expression and their prognostic values for low- and high-grade ovarian serous carcinomas.A total of 38 cases of low-grade and 100 cases of high-grade ovarian serous carcinomas were selected based on the two-tier grading system. Immunohistochemistry was used to detect Pax2, p53 and Ki-67 protein expression in all cases. Correlation of the two-tier system with immunohistochemical results and prognostic parameters were performed.(1) The overall survival, disease-free survival and 5-year survival rates were significantly higher in the low-grade serous carcinoma cases than in the high-grade cases (P < 0.05). (2) Significant differences in protein expressions were found between the low- and high-grade serous carcinomas. The high-grade serous carcinomas had a significantly higher expression level of p53 (55.0% vs 13.2%, P < 0.05) and Ki-67 (42.1% vs 13.7%, P < 0.05), while low-grade carcinomas had a significantly higher expression level of Pax2 (65.8% vs 13.0%, P < 0.05). (3) Pax2 positive cases had a significantly better overall survival and 5-year survival rates than Pax2 negative cases (P < 0.05). The expressions of p53 and Ki-67 were found to have little correlation with overall survival and disease-free survival (P > 0.05).The two-tier system for the grading of ovarian serous carcinomas has a good prognostic value. There are significantly differences in expressions of Pax2, p53 and Ki-67 between low- and high-grade ovarian serous carcinomas. Compared with p53 and Ki-67, Pax2 is likely a better prognostic indicator for ovarian serous carcinoma.

Basal cell carcinoma (BCC) located on the scrotum is rare.To analyze clinical and pathologic features, discuss therapeutic strategies, and identify prognostic factors of scrotal BCC in Chinese patients.Between 2000 and 2010, 10 patients with scrotal BCC were diagnosed and treated at our institution. A review was performed using the clinical records and dermatopathologic slides of these patients.The median patient age was 70. Skin lesions presented as red nodules and brownish plaques. All patients were treated using wide excision without adjuvant therapy. After an average follow-up of 47months, eight patients were in good health without any relapse. One patient developed left inguinal lymph node metastasis at 21months that was successfully treated using bilateral inguinal lymphadenectomy. One patient developed bilateral pulmonary metastasis at 48months and was palliatively treated with chemotherapy. The clinical and histopathologic risk factors predisposing to metastasis were large primary neoplasms; a long period of misdiagnosis; and infiltrating, morpheaform, spiky, irregular outline pathologic patterns.BCC of the scrotum is rare. It can metastasize after a long period of initial therapy. Long-term surveillance including a complete metastatic examination is recommended for these patients.

Pancreatic ductal adenocarcinoma (PDA) has two exceptional features. First, it is a highly lethal disease, with a median survival of less than 6 months and a 5-year survival rate less than 5%. Second, PDA tumor cells are surrounded by an extensive stroma, which accounts for up to 90% of the tumor volume. It is well recognized that stromal microenvironment can accelerate malignant transformation, tumor growth and progression. More importantly, the interaction loop between PDA and its stroma greatly contributes to tumor growth and progression. We propose that the extensive stroma of PDA is closely linked to its poor prognosis. An improved understanding of the mechanisms that contribute to pancreatic tumor growth and progression is therefore urgently needed. Targeting the stroma may thus provide novel prevention, earlier detection and therapeutic options to this deadly malignancy. Accordingly, in this review, we will summarize the mechanism of PDA stroma formation, the role of the stroma in tumor progression and therapy resistance and the potential of stroma-targeted therapeutics strategies.